Key result
Prolyl hydroxylase inhibitors may promote vascular calcification through hypoxia-induced HIF-1 activation, preclinical data show.
Why the study?
Whether prolyl hydroxylase inhibitors used to treat anemia in CKD patients favor the development and progression of vascular calcification remains to be explored.
Does the use of prolyl hydroxylase inhibitors for treating anemia in CKD patients favor the development and progression of vascular calcification?
Does the use of prolyl hydroxylase inhibitors for treating anemia in CKD patients favor the development and progression of vascular calcification?
Highlights a potential mechanistic risk that prolyl hydroxylase inhibitors used for CKD anemia might inadvertently exacerbate vascular calcification by stabilizing HIF-1α.
May warrant caution with prolyl hydroxylase inhibitors in CKD anemia; leaves open clinical impact on vascular calcification pending human data.
Morbidity and mortality of chronic kidney disease (CKD) patients are largely associated with vascular calcification, an actively regulated process in which vascular smooth muscle cells (VSMCs) change into cells similar to osteocytes/chondrocytes, known as trans-differentiation. Cellular and systemic response to low oxygen (hypoxia) is regulated by the prolyl hydroxylase/hypoxia-inducible factor (HIF)-1 pathway. Recent studies highlighted that hypoxia-mediated activation of HIF-1 induces trans-differentiation of VSMCs into bone-forming type through an increase in osteo-/chondrogenic genes. Inhibition of the HIF-1 pathway abolished osteochondrogenic differentiation of VSMCs. Hypoxia strongly enhanced elevated phosphate-induced VSMC osteogenic trans-differentiation and calcification. HIF-1 was shown to be essential for phosphate enhanced VSMC calcification. O2-dependent degradation HIF-1 is triggered by the prolyl hydroxylase domain proteins (PHD). Prolyl hydroxylase inhibitors, daprodustat and roxadustat, increase high phosphate–induced VC in VSMCs, stabilizing HIF-1α and activating the HIF-1 pathway in these cells. Whether the use of these PHD inhibitors to treat anemia in CKD patients will favor the development and progression of vascular calcification remains to be explored.
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Armando Negri (2022) conducted a review in Vascular calcification in chronic kidney disease. Prolyl hydroxylase inhibitors (HIF-1 pathway activation) was evaluated. Preclinical evidence indicates that hypoxia-induced activation of the HIF-1 pathway promotes vascular calcification, raising concerns that prolyl hydroxylase inhibitors may exacerbate this process.
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